Protocol for diaphragm pacing in patients with respiratory muscle

McDermott et al. BMC Neurology 2012, 12:74 http://www.biomedcentral.com/1471-2377/12/74

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Protocol for diaphragm pacing in patients with respiratory muscle weakness due to motor neurone disease (DiPALS): a randomised controlled trial Christopher J McDermott1*, Chin Maguire2, Cindy L Cooper2, Roger Ackroyd3, Wendy O Baird4, Simon Baudouin5, Andrew Bentley6, Stephen Bianchi7, Stephen Bourke8, Mike J Bradburn2, Simon Dixon9, John Ealing10, Simon Galloway6, Dayalan Karat5, Nick Maynard11, Karen Morrison12, Naveed Mustfa13, John Stradling14, Kevin Talbot14, Tim Williams5 and Pamela J Shaw1

Abstract Background: Motor neurone disease (MND) is a devastating illness which leads to muscle weakness and death, usually within 2-3 years of symptom onset. Respiratory insufficiency is a common cause of morbidity, particularly in later stages of MND and respiratory complications are the leading cause of mortality in MND patients. Non Invasive Ventilation (NIV) is the current standard therapy to manage respiratory insufficiency. Some MND patients however do not tolerate NIV due to a number of issues including mask interface problems and claustrophobia. In those that do tolerate NIV, eventually respiratory muscle weakness will progress to a point at which intermittent/overnight NIV is ineffective. The NeuRx RA/4 Diaphragm Pacing System was originally developed for patients with respiratory insufficiency and diaphragm paralysis secondary to stable high spinal cord injuries. The DiPALS study will assess the effect of diaphragm pacing (DP) when used to treat patients with MND and respiratory insufficiency. Method/Design: 108 patients will be recruited to the study at 5 sites in the UK. Patients will be randomised to either receive NIV (current standard care) or receive DP in addition to NIV. Study participants will be required to complete outcome measures at 5 follow up time points (2, 3, 6, 9 and 12 months) plus an additional surgery and 1 week post operative visit for those in the DP group. 12 patients (and their carers) from the DP group will also be asked to complete 2 qualitative interviews. Discussion: The primary objective of this trial will be to evaluate the effect of Diaphragm Pacing (DP) on survival over the study duration in patients with MND with respiratory muscle weakness. The project is funded by the National Institute for Health Research, Health Technology Assessment (HTA) Programme (project number 09/55/33) and the Motor Neurone Disease Association and the Henry Smith Charity. Trial Registration: Current controlled trials ISRCTN53817913. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or the Department of Health.

* Correspondence: [email protected] 1 Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK Full list of author information is available at the end of the article © 2012 McDermott et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Background Motor Neurone Disease (MND) is the third commonest neurodegenerative disease with an annual incidence of 2-3 in 100,000 and prevalence of 5-8 per 100,000 [1-3]. Patients experience increasing muscle weakness affecting the limbs, speech and swallowing, and breathing. As the diaphragm and intercostal muscles become weak patients experience sleep fragmentation and symptoms of carbon dioxide retention. These consist of early morning headaches, unrefreshing sleep and sleepiness during the day [4,5]. These symptoms severely impact on cognition and quality of life [6]. When respiratory muscle weakness is advanced, patients can be breathless at rest and are prone to recurrent chest infections. Severe respiratory muscle weakness is a poor prognostic sign and once the forced vital capacity (a measure of respiratory muscle strength) reaches less than 50% of the predicted value, mortality at 9 months ranges from 60%100% [7,8]. An important advance in the management of respiratory symptoms in MND has been the demonstration of the beneficial effects of non invasive ventilation (NIV). A randomised controlled trial demonstrated a median survival benefit of approximately 7 months (p = 0.006), in MND patients using NIV who had good bulbar function [9]. This survival benefit was accompanied by a significant and sustained improvement in quality of life. As experience with NIV has developed, areas of continuing need have been identified which are not sufficiently addressed by NIV alone: a) MND patients with significant compromise of bulbar function do not tolerate NIV and in the above trial of NIV, no significant survival benefit was demonstrated for this group [9]. b) Similarly some patients fail to tolerate NIV due to claustrophobia and mask interface problems. In addition although the NIV systems are ideal for overnight use, during the day the mask interface can interfere with communication and feeding and the ventilator itself, although small, does restrict mobility. c) Eventually respiratory muscle weakness progresses to a point at which intermittent/overnight NIV is ineffective. There is therefore, a need for additional complementary respiratory support to further aid respiratory muscle weakness and so potentially provide a prolongation of good quality life. Diaphragm pacing (DP) is a technique initially developed for the treatment of respiratory muscle weakness in patients with spinal cord injury [10]. In this patient group it has allowed patients to reduce their time on

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mechanical ventilation or even remove the need for mechanical ventilation [11]. The NeuRX RA/4 System is a four channel percutaneous neuromuscular stimulation system. Intramuscular electrodes are implanted laparoscopically into the abdominal surface of the diaphragm, with leads tunnelled to an exit site on the abdomen. A small external stimulator delivers the stimulus pulses and provides respiratory timing. It is hypothesised that the potential benefits of DP in MND may come from a restoration of the coordination of respiration, lost as a result of upper motor neurone dysfunction, as well as conditioning of diaphragm muscle. In a healthy diaphragm slow twitch type I muscle fibres predominate. Disuse and suppression of the diaphragm activity, due to artificial ventilation, has been demonstrated to lead quickly to atrophy and to a predominance of fast type IIb muscle fibres [12]. The predominant type IIb muscles fibres lead to inefficient uncoordinated diaphragm contractions. In MND a similar process is likely to occur due to disuse (secondary to UMN dysfunction) and suppression of diaphragm activity due to NIV. DP may condition the diaphragm with a conversion back to efficient type I muscle fibres [13]. The anticipated benefits of DP in the MND patient group are: improved survival; improved quality of life; reduction in need for NIV; a less intrusive method of providing respiratory support compared to NIV. Diaphragm pacing

The NeuRx R/A4 device, has been utilized in over 350 patients to date, including two separate investigational device exemption (IDE) trials [14]. There are over 275 patient years of cumulative use of the device with the initial spinal cord injured (SCI) patient utilizing the device continuously for 10 years. Efficacy evidence

A pilot feasibility study of 16 patients with MND implanted with DP demonstrated provisional safety and tolerability data and a decline in forced vital capacity of 0.9% per month following implantation, compared to 2.4% per month before the procedure [13]. One hundred and six MND patients have been implanted with the NeuRX RA/4 Device in a U.S. Food and Drug Administration (FDA) prospective multi-centre trial. The planned primary analysis of this study was the change in rate of decline of FVC between lead-in (3 months) and DP treatment (12 months) phases for patients not using NIV. The full study results have not yet been published. However subgroup data are available following approval of DP for MND patients under the FDA Humanitarian Device Exemption (HDE) Programme [14,15]. For this approval, analysis was performed on a subgroup of patients who met the Humanitarian Use Designation


population criteria (HUD #10-0242) i.e., MND patients with a stimulatable diaphragm by voluntary contraction or phrenic nerve conduction studies, and who were symptomatic due to chronic hypoventilation (CH). The physiological criteria for CH were FVC < 50%, or MIP 6kPa (daytime) f ) Significant overnight O2 desaturation (>5% of night with Sp02